Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary or essential thrombocythemia is rarely observed in childhood, and familial occurrence has been reported only once. In this study, essential thrombocythemia is documented in five members of both sexes from two to 62 years of age in three successive generations. The propositus had a persistent elevation of the platelet count, splenomegaly, a normal hemoglobin level, a normal white blood cell count, and abnormal platelet aggregation. Platelet arachidonic acid metabolites assayed by high-performance liquid chromatography and serum thrombopoietin levels were normal. Megakaryocytes were increased in number and size. Both mature and early immature megakaryocytes, but no atypical megakaryocytes, were identified by surface immunofluorescence. Bone marrow cultures showed normal myeloid and erythroid colony formation, and chromosome studies revealed a normal female karyotype. These findings support the concept that familial essential thrombocythemia is a myeloproliferative disorder that is transmitted by an autosomal dominant mode of inheritance, and that untreated young women and children with essential thrombocythemia have long survival.
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PMID:Familial essential thrombocythemia. 395 24

Several recent studies show that production of platelets and red blood cells (RBC) are inversely related. For example, it is well established that hypoxia, a stimulator of erythropoiesis, causes thrombocytopenia in laboratory animals. The thrombocytopenia is most likely the result of a reduction in the production of platelets caused by a decrease in the number of colony-forming units-megakaryocyte (CFU-Meg), early precursor megakaryocytes (small acetylcholinesterase-positive cells, SAChE+), and recognizable megakaryocytes in the bone marrow. In all cases, active erythropoiesis was required for the thrombocytopenia. The hypoxia-induced thrombocytopenia was not caused by sequestration of platelets in an enlarged spleen or by expanding blood volumes. We speculate that this thrombocytopenia is caused by competition of a precursor cell of the erythrocytic and megakaryocytic cell lines; that is, marked stimulation of the erythroid cells by erythropoietin (Epo) causes a decrease in the number of immature megakaryocytes, leading to decreased thrombocytopoiesis. In support of this hypothesis, other recent work shows that thyroxine (a stimulator of erythropoiesis) and Epo (when given in large, chronic doses) elevate erythropoiesis and cause thrombocytopenia. Conversely, both endogenous and exogenous sources of thrombopoietin lead to elevated thrombocytopoiesis and anemia in mice. It should also be mentioned that megakaryocytes and erythrocytes have several biochemical similarities, and several clinical conditions point to an inverse relationship between RBC and platelet production. These in vivo, biochemical, and clinical data support the hypothesis that megakaryocytes and erythrocytes share a common precursor cell.
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PMID:Megakaryocytic and erythrocytic cell lines share a common precursor cell. 829 32

Agnogenic myeloid metaplasia (AMM) is a disease characterized by bone marrow megakaryocyte hyperplasia and clusters of megakaryocytes, in which many of the megakaryocytes are atypical. In order to elucidate the mechanisms of megakaryocytosis, ELISA assays of blood levels of thrombopoietin (TPO), interleukin-6 (IL-6) and interleukin-11 (IL-11) were done in 45 patients with AMM and compared with normal volunteer controls. Higher blood TPO levels were found in AMM than in controls (P < 0.0001), and blood TPO levels were correlated with the degree of marrow fibrosis (P = 0.0078). Blood levels of IL-6 were also significantly higher in AMM, when compared with controls (P < 0.0001). However, no correlation was found between blood IL-6 levels and degree of marrow fibrosis. No correlation was found between either TPO or IL-6 and the number of blood platelet counts, the number of marrow megakaryocytes, WBC counts, or the degree of splenomegaly. Blood IL-11 levels were undetectable in most patients and no significant difference was found in AMM as compared to controls. The present study demonstrated that, while in idiopathic thrombocytopenic purpura (ITP) or aplastic anemia, blood TPO levels are relatively correlated with the numbers of platelet and/or megakaryocyte mass, blood TPO levels do not correlate with blood platelet counts, or marrow megakaryocyte mass in AMM. Therefore, in AMM, other mechanisms such as the number of TPO receptors on platelets or megakaryocytes, c-MPL receptor abnormalities, abnormal production of TPO mRNA and so on, will have to be studied. Furthermore, TPO may play a significant role in the pathogenesis of marrow fibrosis; IL-6 may be a factor in the development of marrow megakaryocytosis but its elevated blood levels may represent a secondary immune phenomenon; and IL-11 probably does not play a significant role in causing marrow megakaryocytosis in this disease.
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PMID:Blood thrombopoietin, IL-6 and IL-11 levels in patients with agnogenic myeloid metaplasia. 936 14

It is widely accepted that thrombocytopenia associated with liver cirrhosis is caused by increased platelet destruction in the enlarged spleen, but this issue has not yet been analysed sufficiently in terms of platelet production. Thrombopoietin is produced mainly in the liver and strongly promotes platelet production. We studied serum thrombopoietin and the levels of its mRNA in liver tissue of cirrhotic patients and also in a rat model of liver cirrhosis. Furthermore, to clarify the influence of the spleen, we investigated thrombopoietin mRNA in splenectomized rats. The serum thrombopoietin level in humans with liver cirrhosis was not significantly reduced instead of thrombocytopenia. The expression of thrombopoietin mRNA in liver tissue decreased with the progression of liver cirrhosis in both patients and the rat model and no compensatory expression was observed in other organs or non-parenchymal cells. The level of thrombopoietin mRNA did not differ significantly in splenectomized cirrhotic rats before or after administration of dimethylnitrosamine, but was lower than that in splenectomized rats without cirrhosis. We conclude that thrombocytopenia in liver cirrhosis is caused not only by platelet destruction but also by decreased platelet production, perhaps due to reduction of thrombopoietin mRNA in the liver.
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PMID:Reduced expression of thrombopoietin is involved in thrombocytopenia in human and rat liver cirrhosis. 979 89

Using a new adenoviral vector (Ad) construct, we expressed human thrombopoietin (TPO) cDNA (AdTPO) in mice with various inherited immune deficiency syndromes such as nude, SCID and NOD-SCID mice. Immune normal Balb/c mice and a vector construct without TPOcDNA (AdNull), respectively, were used for controls. All animals (3 per group) were treated with a single application of 10(9) PFU (plaque forming unit) of Ad (AdTPO or AdNull) intraperitoneally on day 0. Four to 5 weeks following AdTPO administration, SCID and NOD-SCID mice demonstrated peak concentration of PLT of 12- to 14-fold normal value simultaneously with maximum concentration of PMNs (10- to 12-fold normal value). Later on these animals had a chronic thrombocytosis. In contrast, Balb/c mice and nude mice experienced PLT peak concentration of 4- to 6-fold normal value without granulocytosis 1 to 2 weeks following AdTPO treatment. Only nude mice had chronically elevated PLTs. In contrast, Balb/c mice developed thrombocytopenia due to cross-reacting anti-TPO antibodies. Animals with chronic thrombocytosis revealed increased content of CFU-G/GM, CFU-GEMM and CFU-Meg in bone marrow compared with controls. In contrast, Balb/c mice showed decreased content of CFUs if anti-TPO-antibodies were present. Histologically, only SCID mice developed severe osteomyelofibrosis and osteomyelosclerosis, hepato-splenomegaly, extramedullary hematopoiesis in liver and lung and ultimately suffered of progressive pancytopenia, anisocytosis, fragmentocytosis and a lethal wasting syndrome. In contrast, NOD-SCID mice which demonstrated similar extent of TPO overexpression and in addition to the B- and T-cellular immune deficiency harbour defective monocytes and macrophages, did not develop fibrotic changes of the bone marrow. From these results, we conclude (1) chronic TPO overexpression in vivo may lead to thrombocytosis and granulocytosis with expansion of CFU-GM, -GEMM and -Meg; (2) in vivo expression of adenovirally mediated TPOcDNA depends on immune competency of the host; (3) functionally normal monocytes and macrophages are indispensable for development of secondary osteomyelofibrosis and (4) adenovirally mediated expression of xenogeneic transgenes may brake immune tolerance for the respective self protein leading to autoimmune phenomena. Our in vivo model might provide further insights into the pathophysiology of secondary osteomyelofibrosis and may prove useful in designing new strategies for immune therapies of cancer.
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PMID:[Adenovirus long-term expression of thrombopoietin in vivo: a new model for myeloproliferative syndrome and osteomyelofibrosis]. 982 87

The present study reports the hematopoietic response to the exogenous administration of recombinant rhesus interleukin-3 (rrIL-3) or a combination of recombinant human granulocyte colony-stimulating factor (rhG-CSF)/erythropoietin (Epo)/thrombopoietin (Tpo) at two different stages of SIV infection: Early-stage (n = 6, CD4 + > 1000/microl and mild splenomegaly) and late-stage (n = 6, CD4 + < 500/microl, progressive hepatosplenomegaly and/or weight loss). SIV-infected animals exhibited significantly impaired bone marrow (BM) and peripheral blood (PB) responses to both rrIL-3 and rhG-CSF/Epo/Tpo administration, as compared to historic controls. In addition, compared to early-stage SIV-infected animals, late-stage SIV-infected macaques demonstrated a more marked dysfunction, as assessed by PB and BM CD34 + content and clonogenic progenitors (colony-forming unit). Neither rrIL-3 nor rhG-CSF/Epo/Tpo administration during either early-stage or late-stage SIV infection increased the viral load, as assessed by bDNA assay. These data suggest that hematopoietic reserve and the response to various cytokines is decreased even in early-stage SIV infection, with the hematopoietic dysfunction progressing in parallel to SIV infection.
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PMID:Hematopoietic response to lineage-non-specific (rrIL-3) and lineage-specific (rhG-CSF, rhEpo, rhTpo) cytokine administration in SIV-infected rhesus macaques is related to stage of infection. 1095 Apr 51

Moderate thrombocytopenia is a frequent finding in cirrhosis of the liver and well tolerated in most instances. The pathophysiology of thrombocytopenia in liver disease has long been associated with the concept of hypersplenism, where portal hypertension was thought to cause pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes in the enlarged spleen. The concept of hypersplenism was never proven beyond any doubt but was widely accepted for the lack of alternative explanations. With the discovery of the lineage-specific cytokine thrombopoietin (TPO) the missing link between hepatocellular function and thrombopoiesis was found. TPO is predominantly produced by the liver and constitutively expressed by hepatocytes. TPO production in humans is dependent on functional liver cell mass and is reduced when liver cell mass is severely damaged. This leads to reduced thrombopoiesis in the bone marrow and consequently to thrombocytopenia in the peripheral blood of patients with advanced-stage liver disease. With recombinant TPOs in development, patients with liver disease and TPO seem to be the ideal target population for this drug. Once the efficacy of thrombopoietin in patients with liver disease is proven, a potent yet safe drug may be available to treat cirrhotic patients undergoing invasive or surgical procedures, during bleeding episodes or when undergoing therapy with myelosuppressive drugs such as interferon-alpha.
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PMID:Thrombocytopenia in liver disease. 1111 Jun 14

Splenomegaly is a frequent finding in patients with liver disease. It is usually asymptomatic but may cause hypersplenism. Thrombocytopenia is the most frequent manifestation of hypersplenism and may contribute to portal hypertension related bleeding. A number of therapies are available for treating thrombocytopenia due to hypersplenism including splenectomy, partial splenectomy, partial splenic embolization, TIPS etc. None is entirely satisfactory. Hypersplenism usually improves following liver transplantation. Therapy with cytokines such as thrombopoietin may offer hope for the future. Patients with liver disease also have abnormalities in coagulation. This is not surprising as all coagulation proteins (except for von willebrand factor vWF) and most inhibitors of coagulation are synthesized in the liver. Genetic or acquired abnormalities of coagulation may predispose to thrombosis of the hepatic or portal veins with significant clinical sequelae. An understanding of the mechanisms involved in coagulation and thrombosis is valuable in choosing from the increasing treatment options available. These include clotting factors, haemeostatic drugs and newer therapies such as recombinant factor VIIa. Splenic artery aneurysms are the most common visceral artery aneurysms in man. Rupture is frequently catastrophic. These aneurysms are being increasingly recognized in liver transplant patients and require treatment before or during transplant surgery.
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PMID:Splenomegaly, hypersplenism and coagulation abnormalities in liver disease. 1113 52

Knowledge about synthesis of thrombopoietin (TPO) by human liver cells is now well established and makes the study of TPO serum levels and interdependency with platelet concentrations important before and after liver transplantation. We followed these variables in 14 patients suffering from primary biliary cirrhosis (group A), 10 with hepatitis B (group B) and nine with hepatitis C (group C) infections, as well as 11 patients suffering from alcoholic cirrhosis (group D). In the pretransplant serum samples, TPO levels and platelet counts revealed median values (range) of 112.75 pg/ml (5.0-349.3) in group A, 67.8 pg/ml (14.8-249.9) in B, 68.6 pg/ml (31.4-147.3) in C and 57.9 pg/ml (25.2-264.2) in D for TPO, and 138 x 10(9)/l (36-243) in A, 48 x 10(9)/l (22-129) in B, 105 x 10(9)/l (32-176) in C and 109 x 10(9)/l (33-285) in D for platelets, the latter levels being abnormally reduced. Within 2-3 d of transplantation, the TPO levels started to increase to transient peaks of mostly 5-10 times baseline, which were followed by continuous correction of thrombocytopenia. Splenomegaly was identified to be an important co-factor of thrombocytopenia in groups A and D. We conclude that decreased TPO production in patients with end-stage liver diseases is reverted by orthotopic liver transplantation.
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PMID:Transient thrombopoietin peak after liver transplantation for end-stage liver disease. 1156 98

The pathogenesis of thrombocytopenia in chronic hepatitis is not well known. This study evaluated the relationship between liver injury, serum thrombopoietin, splenomegaly and thrombocytopenia in chronic viral hepatitis. Two hundred and nine patients were enrolled, 85 with splenomegaly and 124 without. Thrombocytopenia was present in 71% and 23% of patients with or without splenomegaly respectively. In subjects with low platelet count, those with splenomegaly showed significantly lower platelet numbers than those without splenomegaly. The spleen size correlated with portal hypertension. An inverse correlation between spleen size and platelet count was observed (r = -0.54; P < 0.0001). In patients without splenomegaly, thrombocytopenia was associated with the grade of fibrosis; platelet counts were the highest in patients with fibrosis 0-2, lower in those with grade 3 (P < 0.008) and lowest in those with grade 4 (P < 0.05). These findings were independent of demographic and biochemical characteristics, hepatic necroinflammatory activity, portal hypertension and splenomegaly. Patients with normal platelet counts showed higher thrombopoietin levels than those with low platelet counts (P < 0.0001). An inverse correlation between thrombopoietin levels and fibrosis grade was observed (r = - 0.50; P < 0.0001). Median thrombopoietin levels were 58 and 27 pg/ml for fibrosis grade 0-1 and grade 4 respectively (P < 0.001). These data indicate that advanced hepatic fibrosis, causing an altered production of thrombopoietin and portal hypertension, plays the central role in the pathogenesis of thrombocytopenia in chronic viral hepatitis.
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PMID:Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis. 1138 Apr 42


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